The long-term goal of this work is to understand the principles of control of neurophysiological systems by neuromodulators. Neurophysiological systems are complex, with many components connected by reciprocal interactions and feedback loops into coherently acting networks. When such a system is modulated to alter its function, the interconnected network architecture of the system places fundamental constraints on the ways in which the modulation can be effectively accomplished. In particular, simultaneous modulation of multiple components of the network is required to achieve stable, precisely coordinated changes in certain components while avoiding unwanted changes in others. Here the logic of such modulation will be studied in the cardiac system of the blue crab, a simple model system in which all components are already relatively well known and open to inspection and manipulation. The heartbeat is driven by the cardiac ganglion, a very simple central pattern generator (CPG) that lies within and controls the heart musculature. The contractions of the heart, in turn, adjust parameters of the motor program of the CPG. Numerous modulators present in the system alter multiple parameters of the motor program and contractions to achieve coherent regulation of the heartbeat and cardiac output in distinct, sometimes diametrically opposed ways. In this proposal, the modulated CPG-muscle network will be investigated using mathematical modeling and theory together with complementary experiments. First, on the basis of detailed experimental data, a mathematical model of the unmodulated system will be developed. Second, the structure of the modeled network will be studied using techniques from control theory and dynamical systems theory. Finally, the model will be modified to include the effects of modulation so that its role may be analyzed. At each stage, the analysis will make predictions that will be experimentally tested in the real system. PUBLIC HEALTH RELEVANCE The broader significance of this work will be two-fold. First, the work will reveal some of the principles of the functional control of networks generally. Second, it will further our understanding of how, using these principles, nervous systems control functional behavior. In view of the conservative approach that nature commonly takes toward problem-solving, it is likely that the mechanisms and principles revealed in this simple system will be reflected in more complex neuronal networks and brains, including the human brain and nervous system. Since such networks control vital functions such as breathing, feeding, and locomotion, this analysis will make an important contribution toward understanding how such behaviors are controlled by the nervous system, how this control can break down, and how function can perhaps be restored.